Efficacy of cryotherapy on chemotherapy-induced peripheral neuropathy in patients with breast cancer: a propensity score-matched study

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent unfavorable side effects. CIPN refers to the loss of peripheral nerve function that certain types of chemotherapy can cause. Objective: This study investigated the effectiveness of cryotherapy in preventing CIPN and its effect on the quality of life (QoL) during chemotherapy. Methods: Eligible participants are cancer patients who began therapy with carboplatin, docetaxel, or paclitaxel in the Breast Oncology Unit between May 2022 and October 2022. Patients were distributed into intervention groups that utilized cryotherapy with ice gloves and ice boots and control groups that did not receive cryotherapy. Patient self-report questionnaires were used to quantify patients’ symptoms and QoL after treatment. Results: The intervention group exhibited significantly less cold sensitivity, hand and foot numbness, and hand tingling than the control group. Daily CIPN symptoms were substantially milder in the intervention group. Before and after treatment, nerve pain, balance, and muscle and joint discomfort were similar. Intervention and control groups have varied neurotoxicity adverse reaction scores. 2.4% of controls had grade 4 motor neurotoxicity impairment. Physical function and QoL improved in the intervention group. Conclusions: Cryotherapy relieves CIPN symptoms in breast cancer patients receiving carboplatin and paclitaxel chemotherapy. More thorough trials should be carried out to determine the best time limit and duration of cryotherapy.


Introduction
Globally, adjuvant systemic therapy has greatly enhanced breast cancer survival [1] . It has been demonstrated that adjuvant chemotherapy reduces the risk of breast cancer recurrence and mortality [2] . Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent side effects in chemotherapy patients [3] . The overall incidence of CIPN in cancer patients is more than 60% [4] , and 20-30% of patients are long-term sufferers [5,6] . CIPN is the deterioration of peripheral nerve function caused by specific chemotherapy medications (such as oxaliplatin, taxanes, vinblastines, etc.) [7] . CIPN may give rise to a range of sensory, motor, and autonomic manifestations. These may include symmetrical numbness, tingling, heightened sensitivity to cold and temperature, and muscle weakness in the extremities [8][9][10] . Seretny's Meta-Analysis revealed that oxaliplatin, paclitaxel, and cisplatin/carboplatin combined with paclitaxel caused CIPN in 72.3%, 70.8%, and 73.0% of patients, respectively [9] . In addition, CIPN might manifest minutes after chemotherapy and disappear within 2-3 days [11] , or it can persist decades after chemotherapy has ended [12][13][14] . The use of freezing gloves and socks reduced the likelihood of docetaxel-induced CIPN by 44%, according to an exploratory trial [15] . Cryotherapy not only inhibits the release of vasodilation chemicals, hence decreasing the sensitivity of pain receptors, but it also decreases muscle spasms by decreasing nerve conduction velocity and muscle excitability [16] . Regional hypothermia therapy can reduce regional perfusion, metabolic rate, and cell chemical activity in order to alleviate chemotherapyrelated symptoms [17] . There are many studies showing similar HIGHLIGHT • Patients who underwent chemotherapy with medicines such as oxaliplatin and paclitaxel were shown to be more likely to suffer from peripheral nerve illnesses, according to the findings of our clinical nursing work. • We intervened in patients using freezing gloves and freezing socks. • Cryotherapy has a beneficial therapeutic effect on the prevention of CIPN, which has important repercussions for the patients. a benefits of using cryotherapy for the prevention of CIPN; unfortunately, no consensus exists about the therapeutic value of cryotherapy [18][19][20][21][22] . In light of the correlation between ethnicity and temperature sensitivity, and the lack of a corresponding report in China, a clinical study was conducted to investigate the effectiveness of cryotherapy, specifically the use of freezing gloves and socks, in mitigating CIPN among breast cancer patients undergoing paclitaxel and platinum-based chemotherapy. And our research hypotheses are that in breast cancer patients taking chemotherapy, cryotherapy has a significant benefit in preventing CIPN.

Study design
This study is a prospective trial undertaken at a Cancer Center of a Medical University. The Institutional Review Board approved this study, and written informed permission was obtained from all participants. This study was performed in line with the principles of the Declaration of Helsinki.

Participants
All adult patients diagnosed with breast cancer at the Breast Oncology Unit of the Center between May and October 2022 and treated with carboplatin, docetaxel, or paclitaxel are eligible to participate in this study. If the patient has other causes of peripheral neuropathy, such as diabetes, infection, radiotherapy, poisoning, alcoholism, etc., or if they have peripheral sensory abnormalities, aberrant neurological illnesses, or are receiving other neurotoxic medicines, they will be excluded. After verifying that the patients were eligible, the grouping of the patients was carried out using the random number table approach. Patients were randomly randomized to cryotherapy with frozen gloves and socks or a control group that did not get cryotherapy. The patients will be segregated into two distinct nursing cohorts for the purpose of therapy subsequent to group allocation, with the aim of reducing the impact of contamination.

Sociodemographic and clinical characteristics
The clinical and sociodemographic features of patients were taken from their medical records. Comorbidities were assessed through the use of a self-reported comorbidity questionnaire in addition to an examination by a professional nurse.

Cryotherapy intervention
The intervention group applied cryotherapy to the hands and feet of patients using cryo gloves and socks. The outside material of frozen gloves and stockings is thermoplastic polyurethane. Additionally, polyacrylic polyol polymer is used inside as a refrigerant for freezing. To get the optimal ideal temperature, place the gloves in a − 20°C freezer for at least 3 h before usage. The subjects wore freezing gloves and socks from 15 min prior to chemotherapy infusion to 15 min after chemotherapy infusion and continued to wear the device during treatment. Paclitaxel is typically administered within 30 min; therefore, cryotherapy typically lasts 60 min. Gloves and socks can be kept at a temperature of between − 10 and 4°C when in use. At regular intervals of 45 min, the cryostat was substituted to uphold optimal vasoconstrictive cryogenic temperatures. Furthermore, as a measure of hygiene, the participants utilized disposable nitrile gloves and polypropylene sock liners within their gloves and socks, correspondingly. Participants with cryotherapy intolerance were permitted a brief pause during cryotherapy administration.

CIPNAT
Tofthagen et al. [23] developed Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (CIPNAT) in 2008 as a patient selfreport questionnaire that can completely measure the incidence of CIPN in cancer patients. The scale consists of two parts: the first is the patient's experience with CIPN symptoms, and the second is the influence of CIPN on the patient's everyday activities. CIPN symptom experience consists of nine symptoms, which are separated into two categories of sensory and motor nerve injury, with a total of 36 subitems rating symptom occurrence, severity, degree of distress, and frequency of occurrence, yielding a total score of 0-279 points. The higher the score, the more severe the patient's CIPN symptoms. The influence of CIPN on the quality of life (QoL) of patients is measured along two dimensions -fine motor and general activitieswith a total of 14 items yielding a score between 0 and 140. The greater the total score, the greater the daily effect of symptoms. This study employs the Chinese version of the CIPNAT, which preserves all the original items of the original scale and maintains the original scoring procedure and dimension divisions. In the Chinese version, the test-retest reliability of each subscale and the overall scale is between 0.89 and 0.93, the Cronbach's coefficient is between 0.891 and 0.941, and the content validity index is between 0.89 and 1. Exploratory factor analysis reveals that the factor loading of each item is greater than 0.4 and that the cumulative contribution rate is 57.46%, indicating that the Chinese version of the CIPNAT is reliable and valid.

QoL
In this study, the EORTC QLQ-C30 was utilized to assess the QoL of patients. The scale consists of 30 items and 15 domains, comprising 5 functional subscales, 3 symptom subscales, 6 individual measurement items, and 1 domain assessing general health status. In addition to the overall QoL rating, which ranged from 1 ('extremely poor') to 7 ('outstanding'), each item was assessed using a Likert scale ranging from 1 ('not at all') to 4 ('very much'). The scores of each subscale were transformed to a scale ranging from 0 to 100, with higher scores indicating a higher QoL. Wan reported that the Chinese version of EORTC QLQ-C30 was used in our research. Both the internal consistency and test-retest reliability of the Chinese version are more than 0.70, showing that it is reliable, valid, and feasible.

The incidence of CIPN
The National Institutes of Health (NIH) and the National Cancer Institute (NCI) completed a revision of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE 5.0) in 2017. This version is the most recent revision of this document. The grading standard for peripheral neurotoxicity was utilized in this study to analyze the incidence of central and peripheral neuropathy (CIPN) in patients and to rate the adverse reactions that manifested themselves in each system [24] .

Statistical analysis
Using the PASS software, the sample size can be estimated based on the following assumptions: the predicted dropout rate of the sample is 20%, the significance level = 0.05, the test power is 0.80, and the significance level = 0.05. As a result, there were a minimum of 45 samples included in each of the groups, in order to make the matching more accurate, the sample size of the control group and the intervention group was set to 2:1; for a total of 135 instances.
IBM SPSS 26.0 was used to conduct all of the statistical analyses. Depending on whether or not the continuous data were regularly distributed, the mean, standard deviation, or interquartile range (IQR) was used to summarize them. If the data were not normally distributed, the median was used. The results of categorical research are often displayed using counts (N) and percentages (%). The self-reported outcomes of CIPNAT and QoL in the experimental and control groups before and after chemotherapy were subjected to one-way analysis of variance (ANOVA) testing to determine whether or not they were independent.
In order to correct for any imbalance caused by the use of subjective patient self-report questionnaires, propensity score matching (PSM) will be used in addition to a thorough analysis of all measurement findings. The propensity score for this study was calculated using six predetermined covariates: patient age, sex, tumor metastasis, chemotherapeutic regimen, and CIPNAT, or NCI-CTCAE score baseline. The closest  propensity score was utilized in a greedy 1:1 algorithm to pair patients getting cryotherapy with those in the control group for each pair of patients.

Sociodemographic and clinical characteristics
There were a total of 135 breast cancer patients enrolled in the study. Seven patients withdrew from the study after randomization due to changes in chemotherapy regimen or inability to endure cryotherapy (Fig. 1). The age of 122 breast cancer patients is 49.93 10.74 years old; there were no significant sociodemographic or clinical differences between the intervention groups and control groups. They all received systemic chemotherapy, including nab-paclitaxel, paclitaxel, docetaxel, and carboplatin. The medical information and features of the individuals in the study are presented in Table 1.

PSM
The intervention group and the treatment group's propensity scores were matched, resulting in 42 subject groups with matched clinical information and baseline peripheral nerve function. These matched patients' CIPNAT self-report scores and NCI-CTCAE scoring were not significantly different (P > 0.05). Table 2 contains a list of the precise baseline data. After PSM, baseline data from the intervention and control groups are matched (CIPNAT and NCI-CTCAE)

CIPN
The CIPNAT self-report questionnaire was used to make comparisons on the prevalence and severity of CIPN among the study participants (Table 3). In terms of symptoms, those in the intervention group experienced less cold sensitivity (P = 0.022), numb hands (P < 0.001), numb feet (P < 0.001), and tingling hands (P = 0.011) than those in the control group. In all, 90% and 85% of patients in the control groups experienced numbness in their hands and feet, whereas only 54.8% and 42.9% of patients in the intervention group experienced this symptom. After chemotherapy, the intervention group reported lower total symptom scores, indicating that their symptoms were less severe than those reported by the control group. There was not a significant difference between the scores of nerve pain (P = 0.17), loss of balance (P = 0.522), foot tingling (P = 0.537), and muscle and joint pain (P = 0.488) before and after chemotherapy in the intervention group and the control group. Those results indicated that those in the intervention group were significantly less impacted by the symptoms of CIPN on a day-to-day basis when compared to those in the control group (19.33 vs. 35.22, P = 0.032). It was discovered that the patients in the control group were more severe and deteriorated than the intervention group, whether in terms of the symptoms of neuropathy or the impact of neuropathy on life after PSM was employed to address the baseline imbalance (Fig. 2).

CIPN symptom burden (NCI-CTCAE)
Tumor specialist nurses examined and graded each patient's CIPN symptoms in accordance with NCI-CTCAE criteria on the day before chemotherapy and the seventh day after chemotherapy. The total incidence rate of sensory neurotoxicity before therapy was 61.54%. The values are 48.19% and 38.55% for motor neurotoxicity and neuralgia, respectively (Table 4). Overall, the intervention group's symptom score stayed below grade 3, and the great majority of patients' ratings were only rated 1 or 2. As a result, the motor neurotoxicity component in the control group was severely impaired in 2.4% of patients, earning it a grade of 4. After adjusting for baseline differences, motor abnormalities worsened considerably more in the control group than in the intervention group, although sensory abnormalities and neuralgia did not differ significantly (Fig. 3).

QoL
In order to determine the subjects' overall QoL, a questionnaire based on the EORTC QLQ-C30 scale was employed for each participant. A comparison of the rise or reduction in their patients' self-reported QoL scores before and after chemotherapy was made between patients in the intervention group and control group ( Table 5). The intervention group did much better in the functional categories. The scores of those in the intervention group were significantly higher than those in the control group in a number of categories, most notably physical function (85.87 vs. 82.76, P = 0.004) and global QoL (65.08 vs. 50.20, P < 0.001).
Regarding the pain symptoms associated with CIPN, the severity of symptoms was significantly higher in the control group than that in the intervention group (35.77 vs. 14.68, P < 0.001 for both comparisons). Those results suggested that breast cancer patients undergoing chemotherapy may benefit from the utilization of cryotherapy, particularly in terms of their QoL. Figure 2. Mean chemotherapy-induced peripheral neuropathy symptom experience and interference scores were compared between the intervention and control groups after propensity score matching.

Discussion
Breast cancer patients undergoing chemotherapy may benefit from CIPN prophylaxis with cryotherapy, according to our results in this randomized controlled trial. Not only does it alleviate some symptoms in the hands and feet (such as tingling, numbness, and other similar sensations), but it also improves one's overall QoL. It is well known that the pathophysiology of CIPN is quite complex and involves many factors, which is caused by various types of chemotherapy drugs. Patients receiving high doses and multiple courses of therapy were more likely to develop CIPN [25] .
Among female breast cancer patients receiving chemotherapy, older age, higher total paclitaxel dose, history of female hormonerelated diseases, hypertension, and BMI should all be considered as risk factors for the development of CIPN [26] . Based on the pathogenesis of CIPN, a large number of compounds have been used to prevent or treat CIPN by blocking ion channels, targeting inflammatory cytokines, and resisting oxidative stress [27] . An invivo study showed that localized hypothermia reduced sciatic nerve blood flow and neuronal metabolism in rats, implying reduced cumulative doses of toxic chemotherapy near distal nerve fibers [28] .
Worldwide, various studies have confirmed the effect of cryotherapy on the prevention of CIPN. In a Singapore study [29] , cryotherapy individuals showed larger amplitudes of sympathetic skin responses (β = 0.544, 95% CI = 0.108-0.98, P = 0.014), suggesting a possible autonomic benefit of cryotherapy. However, 80.9% of the subjects temporarily ceased cryotherapy due to cold intolerance. A Japanese study demonstrated that cryotherapy could avoid the objective and subjective symptoms of CIPN and the resultant dysfunction study of 40 patients [18] . A Danish study found that patients wearing freeze gloves and socks/socks had less neuropathy during docetaxel treatment than controls [15] .
In addition, the findings of certain studies have been negative. According to the results of a research project conducted in the United States, there did not appear to be any significant difference between cryotherapy and compression therapy in terms of the frequency of CPIN [30] . Physical activity was found to be more helpful than the application of cold compresses in a trial conducted in Turkey including 90 patients [31] . The researchers found that exercise considerably reduced the CIPN symptoms of hand and foot numbness (P = 0.009). When comparing patients in Canada who were given cryotherapy to patients who were given a placebo control, researchers in Canada observed no significant difference in EORTC QLQ CIPN-20 symptom scores at any time point between the two groups [32] .
According to our research findings, cryotherapy was beneficial for breast cancer patients receiving chemotherapy medicines. Table 5 The quality of life of intervention group and control group before and after cryotherapy (EORTC QoL C30 Patient Self-report Score)  Patients diagnosed with breast cancer who took part in the study and got cryotherapy had, on average, fewer symptoms associated with CIPN following chemotherapy than the patients in the control group did. In terms of QoL, the functional status and QoL of patients in the control group were limited to varying degrees due to the probable influence of CIPN symptoms. On the other hand, this did not occur in the intervention group. On the other hand, the QoL of those who participated in the intervention was either largely preserved or slightly improved. In addition, our research found no instances in which cryotherapy had to be stopped because the patient was unable to tolerate the cold. These observations may be impacted by the length of time spent cooling, the temperature, or the method, all of which call for further investigation. In comparison to the findings of previous researchers, our team found that cryotherapy only needed to be administered for a shorter amount of time overall. The use of freezing gloves and freezing socks was begun about 15 min prior to chemotherapy and continued for the full 30 min following treatment; this may be a significant influence in enhancing patient tolerance.
This study also has some limitations. Patients in the intervention group may be more motivated to fill out the questionnaire because they have high hopes that the treatment will be neuroprotective and help them experience a reduction in the symptoms associated with CIPN. It is possible that patients who turned down the opportunity to take part in the trial were unaware of the selection bias that occurred. The symptoms of CIPN are subjective, and in order to evaluate them, we used patient questionnaires in which they described their symptoms, as well as concurrent examinations of their symptoms by nurses. However, these evaluations are the product of the patient or nurse making a subjective assessment, even though it is based on the patient's actual experience of the symptoms. It is possible that this affected the findings of the study. We are unable to perform an objective assessment of the patient's neurological function via objective markers such as electrophysiology due to technical limitations. This is the most significant shortcoming of the study.

Conclusion
The present investigation aimed to assess the potential of cryotherapy, specifically utilizing ice gloves and boots, in mitigating CIPN symptoms among female breast cancer patients. The implementation of cryotherapy has demonstrated an enhancement in the symptoms of CIPN and the overall QoL in patients undergoing chemotherapy treatment with carboplatin and paclitaxel.

Ethical approval
This study has been approved by the Institutional Ethics Committee. Institution Name: Medical Ethics Committee, Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, China; No.: A2021381, date: 23 November 2020.

Consent
Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Sources of funding
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author contribution
M.X.: conceptualization, data curation, methodology, and project administration; F.W.: data curation, project administration, resources, writingoriginal draft, and writingreview and editing; M.X. and F.W.: have the same contribution to this study; X.Z.: methodology and resources; Z.H.: software, validation, and visualization. All authors read and approved the final manuscript.